1. Field of the Invention
The present invention relates to new farnesylated tetrahydro-naphthalenols, which are useful for cholesterol/lipid lowering in cases of hypercholesterolemia, hyperlipidemia, and atherosclerosis. Also provided are pharmaceutical compositions and a method of use employing those compositions.
2. Description of the Prior Art
It is generally recognized that high blood cholesterol levels are a significant risk factor in cardiovascular disease. Studies have demonstrated that with very few exceptions, populations which consume large quantities of saturated fat and cholesterol have relatively high concentrations of serum cholesterol and high mortality rate from coronary heart disease. (The Expert Panel "Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and the Treatment of High Blood Cholesterol in Adults," Arch. Intern. Med. 148, 36-39, (1988)).
It has been established that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the first rate limiting enzyme in the biosynthetic pathway for cholesterol, that inhibition of HMGR activity results in a decrease in serum total cholesterol and LDL cholesterol levels, and that a decrease in serum LDL-cholesterol levels is reflected in a reduction of plasma level of apolipoprotein B. (Brown, et al, J. Lipid Res, 21: 505-517 (1980)).
Tocotrienols have been shown to suppress HMGR resulting in the inhibition of cholesterol biosynthesis and a subsequent drop in LDL cholesterol, apolipoprotein B, thromboxane B.sub.2, platelet factor 4 and glucose levels. (Wright, et al, A Symposium On Drugs Affecting Lipid Metabolism, Houston, Tex. (November 1989)). In J. Biol. Chem261: 10544-10550, (1986), Qureshi, et al. indicated that the hypocholesterolemic effects of alpha-tocotrienol is brought about by the suppression of HMGR as measured by hepatic HMGR activity. (Qureshi, et al, J. Biol. Chem, 261: 10544-10550, (1986)). Wright et al, supra, showed that tocotrienol-rich fraction (TRF) fed to hypercholesterolemic swine resulted in a dramatic decrease in serum total cholesterol and LDL-cholesterol levels. Qureshi, et al, showed that gamma and delta-tocotrienols suppress HMGR activity. (Qureshi, et al, Suppression of Cholesterolgenesis in Hypercholesterolemic Humans by Tocotrienols of Barley and Palm Oils, presented at the Antioxidant and Degenerative Diseases Conference, Berkeley, Calif., (January, 1990)). U.S. Pat. No. 4,603,142 to Qureshi et al., (1986) discloses the use of alpha-tocotrienol for the lowering of lipids.
The tocotrienols are structurally related to the tocopherols (vitamin E) and differ only by possessing unsaturation in the isoprenoid side chain. Like the tocopherols, the tocotrienols have antioxidative activity, (Yamaoka, et al, Yukagaku, 34: 120-122 (1985)). Active oxygen species are known to play pivotal roles in the genesis of atherosclerotic plaques, thrombotic episodes, ischemic damage, cancer, aging, dementia, and inflammatory conditions. (Sies, H., Oxidative Stress; Academic Press, New York, (1985); Santrucek, M., Krepelka, J., Drugs of the Future, 13: 973-996 (1988)). Of particular interests are the potential protective effects of antioxidants on lipoproteins, since oxidized LDL is thought to be atherogenic. (Buckley, M., Goa, K. L., Price, A. H., Brogden, R. N., Drugs. 37: 761-800 (1989); Gwynne, J. T., Schwartz, C. J., Am. J. Cardiology, 62: 1B-77B (1988)). The antioxidative activity of the tocotrienols may be of value in conjunction with their hypolipidemic properties.
A possible liability with the tocotrienols is metabolism of the highly electron-rich benzopyran nucleus. This could lead to oxidative opening of the pyran ring, additional ring hyroxylation and finally excretion via bioconjugation reactions. Our objective was to find analogues possessing greater metabolic stability. The carba-tocotrienol analogs were found to exhibit enhanced lipid lowering activity relative to the tocotrienols as measured in vivo.
The present invention describes the synthesis and preliminary biological evaluation of new farnesylated tetrahydro-naphthalenols analogs.